Toll-like receptors (TLRs) play a crucial role in pathogen recognition and activation of innate and adaptive immune responses to infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. We have recently found that recognition of commensal bacteria by TLRs is critical for the maintenance of intestinal homeostasis, tissue repair and protection from injury. On the other hand, dysregulated responses to commensal bacteria can lead to inflammatory diseases, such as inflammatory bowel disease (IBD). The role of TLRs in the initiation and pathogenesis of IBD is currently unknown. The goal of this proposal is to investigate the role of commensal-TLR interactions in the maintenance of intestinal homeostasis, tissue protection and repair, and the pathogenesis of IBD. We will generate mice that are selectively sufficient or deficient in TLR signaling in different cell types present in the intestine. Using these mice we will investigate the role of different cell types and gene products in recognition of commensal bacteria, host defense, intestinal homeostasis and tissue protection and repair. We will also examine the role of TLRs in the etiology of commensal dependent, T cell mediated colitis model and examine the contribution of TLR signaling by different cell types to pathogenesis. We will analyze the TLR-dependent pathways that are negatively regulated by IL-10 in the colon, and investigate how dysregulation of these pathways leads to initiation and maintenance of colitis. These studies will provide novel and important information that will help elucidate the role of TLRs in intestinal physiology, the pathogenesis of IBD and the biology of host-commensal interactions.